A-homo-delta1, 4, 5(10)-estratrien-3-ones and their preparation



United States Patent O1 hce 3,410,874 Patented Nov. 12, 1968 18 Claims. 61. 260-3459) ABSTRACT OF THE DISCLOSURE This application is a continuation-in-part of my copending US. patent application Ser. No. 302,719, filed Aug. 13, 1963, now abandoned.

This invention relates to novel cyclopentanopolyhydrophenanthrene derivatives and to processes for the prepara tion thereof.

More particularly, this invention relates to novel A- homo-A -estratrien-S-ones represented by the general formula:

R p I In the above formula, R represents a hydroxyl group, an acyloxy group, a tetrahydrofuranyloxy group or a tetrahydropyranyloxy group, R represents hydrogen, a lower alkyl group, such as methyl, ethyl, propyl, and the like, a lower alkenyl (including halo-lower alkenyl) group, such as vinyl, trifluorovinyl; 3fiuoropropenyl, 3,3, 3-trifluoropropenyl, and the like, or a lower alkynyl (including halo-lower alkynyl, hydroxypropynyl and acyloxypropynyl) group, such as ethynyl, chloroethynyl, bromoethynyl, propynyl, monofluoropropynyl, trifiuoropropynyl, butynyl, hexynyl, and the like, and R and R taken together represent a keto group.

The acyloxy and acyl groups referred to herein are preferably derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms. These acids can be saturated or unsaturated (including aromatic), and can be straight-chain, branched, cyclic or cyclic-aliphatic. In addition, they can be unsubstituted or substituted with functional groups such as hydroxyl groups, alkoxy groups containing up to 6 carbon atoms, inclusive, acyloxy groups containing up to 12 carbon atoms, inclusive, nitro groups, amino groups or halogen atoms. Included among such ester groups are the acetate, trimethylacetate, t-butylacetate, phenoxyacetate, aminoacetate, propionate, cyclopentylpropionate, fl-chloropropionate, ena-nthate, adamantoate and benzoate groups.

The compounds represented by Formula A hereinabove are anabolic agents which also have anti-gonadotrophic and anti-fibrillatory properties. In addition,'they are useful in fertility control, lower blood cholesterol levels, relieve premenstrual tension and diminish the output of the pituitary gland.

The compounds represented by the above formula wherein R is other than hydroxypropynyl or acyloxypropynyl are prepared by a process illustrated by the following equation: p

HaGO- I H 300 II H300 IV P- HaCO- III H3CO- V b HaCO- VI X1L X-C! 2': it

O OH I lfj l VII VIII X-C J;

(RR: u

In the above formulas, R represents hydrogen, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group other than hydroxypropynyl and acyloxypropynyl, R represents hydrogen, an acyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group, and X represents a halogen, i.e., fluorine, chlorine, bromine or iodine.

In practicing the process outlined above, the starting material I, a 3-lower alkyl ether of estrone, e.g., estrone 3-methyl ether, is ketalized in known manner as by using a lower alkylene glycol such as ethylene glycol, propylene glycol, or the like in the presence of a catalytic amount of a strong acid, such as p-toluenesulfonic acid or the like, to give the corresponding 17-ketal II, e.g., 17-cycloethylenedioxy-3-methoxy-A -estratriene.

The l7-ketal, dissolved in an ether such as diethyl ether or the like, is then treated with metallic lithium in liquid ammonia, under substantially anhydrous conditions at room temperature to give the corresponding A -diene III, e.g., 17-cycloethylenedioxy-3-methoxy-A -estradiene, which is then reacted with potassium t-butoxide in a hydrocarbon sulfoxide, such as dimeth-ylsulfoxide, methylethylsulfoxide, tetramethylenesulfoxide, or the like, under an inert nitrogen atmosphere at room temperature for about 6 hours or longer, to give the corresponding A -diene IV, e.g., l7-cycloethylenedioxy-3-methoxy- A -estradiene.

The thus-obtained A -diene, dissolved in an inert organic solvent, e.g., an ether such as diethyl ether, dioxane or tetrahydrofuran, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, as well as mixtures thereof, containing potassium t-butoxide, is reacted at a temperature of from about -20 C. to about room temperature, with stirring for from about 1 to about 12 hours under substantially anhydrous conditions in an inert nitrogen atmosphere, with a dihalocarbene, i.e., difluorocarbene or dichlorocarbene, which can be prepared by ther mal decomposition of the sodium salt of chlorodifiuoroacetic or trichloroacetic acid, respectively, or dibromocarbene or diiodocarbene, which can be prepared in situ by the addition of bromoform or iodoform, respectively, to the reaction mixture, thus giving the corresponding 3,4- dihalomethylene intermediate V, e.g., 17-cycloethylenedioxy-3,4-dibromomethylene 3 methoxy A estrene (V; X=bromine).

The 17-ketal group in this 3,4-dihalomethylene intermediate is then hydrolyzed in known manner, e.g., using hydrochloric acid, oxalic acid, or the like, to give the corresponding 17-keto steroid VI, e.g., 3,4-dibromomethylene- 3-methoxyA -estren-l7-one (VI; X=bromine).

By reacting this l7-keto steroid with a silver salt, preferably one which is soluble in water, such as silver nitrite, silver perchlorate, silver acetate, and the like, in water, preferably in the presence of a water-miscible organic solvent, i.e., a lower alkanol such as methanol or ethanol, a ketone such as acetone, or the like, as well as mixtures thereof, at reflux temperature, for from about 25 minutes to about 3 hours. A-homo-A -estratriene-3,17-dione (VII) is obtained. Where the dihalocarbene adduct VI reacts only sluggishly with silver ion, it can be exposed to boiling pyridine for about 1 hour prior to reaction with the silver salt.

Where a 17a-unsubstituted-17,8-hydroxy final product is desired, the 17-keto steroid VI is reduced, preferably using sodium borohydride in tetrahydrofuran-methanol at room temperature for about 12 hours or longer, thus giving the l7ot-unsubstituted-l7fi-ol VIII, e.g., 3,4-dibromomethyl-3- methoxy-A -estren-17fi-vol (VIII; R =hydrogen, X= bromine), which is then treated with a silver salt in water in the manner described hereinabove to give A-homo- A -estratrien-17/8-ol-3-one (IX; R and R =hydrogen).

The corresponding 17-esters are prepared in known manner by reacting the 17u-unsubstituted-17/3-ol 1X with an acyl anhydride or chloride in pyridine at room temperature overnight. Thus, for example, by reacting A- homo-A -estratrien-l7/3-ol-3-one with acetic anhydride in pyridine at room temperature overnight, A-homo- A -estratrien-17 3-ol-3-one 17-acetate (IX; R =hydrogen, R =acetyl) is obtained.

Similarly, the 17a-unsubstituted-l7fl-ol IX (or a substituted 17B 01 IX wherein R =hydrogen) can be etherified with dihydrofuran or dihydropyran by reaction in benzene, under substantially anhydrous conditions, in the presence of an acidic catalyst, e.g., p-toluenesulfonic acid, boron trifluoride etherate, or the like, preferably at from about room temperature to about 50 C. for from about 1 to about 72 hours, thus giving the corresponding l7fl-tetrahydrofuranyloxy or l7/3-tetrahydropyranyloxy steroid IX, e.g., A-homo 17,8 tetrahydropyranyloxy- A -estratrien-3-one (IX; R =hydrogen, R =tetrahydroyranyl) Where the l7a-lower alkyl-, l7ot-lower alkenyl (including halo-lower alkenyl) and 17a-l0W61 alkynyl-17,8-hydroxy final products are desired, the 17-keto steroid VI can be reacted at reflux temperature in an inert organic solvent, preferably thiophene-free benzene, under substantially anhydrous conditions for about 3 hours or longer, with a lower alkyl, alkenyl or alkynyl magnesium halide, such as methylmagnesium bromide, vinylmagnesium bromide, trifluorovinylmagnesium bromide, ethynylmagnesium bromide, or the like, to produce the corresponding 17a-lower alkyl, -lower alkenyl or -lower alkynyl-17B- hydroxy derivative VIII, e.g., 3,4-dibromomethylene-3- methoxy-l7ot-methyl-A -estren 17/3 01 (VIII;- R methyl, X=bromine), which is then treated with a silver salt in water in the manner described hereinabove to give the corresponding A-homo-A -3-one IX, e.g., A- homo-17a-methyl-A -estratrien--01- 3 one (IX; R methyl, R =hydrogen) Similarly, the l7-keto steroid VI can be converted to the corresponding 17a-lower alkyl, -lower alkenyl or -lower alkynyl-l7/3-ol VIII by reacting it with a lower alkyl, alkenyl or alkynyl lithium compound in absolute diethyl ether under an inert nitrogen atmosphere at room temperature for 48 hours or longer. The 17-keto steroid VI, dissolved in anhydrous benzene containing potassium t-amylate, can also be reacted with gaseous acetylene under an inert nitrogen atmosphere at room temperature for 36 hours or longer to give the corresponding 17a-ethynyll7fi-hydroxy steroid VIII. Hydrogenation of this compound or the corresponding A-homo steroid by known means, e.g., using gaseous hydrogen and a suspension of prehydrogenated 2% palladium-on-calcium carbonate hydrogenation catalyst in pyridine at room temperature and atmospheric pressure until approximately 1.1 molar equivalents of hydrogen are absorbed for partial hydrogenation or gaseous hydrogen and a suspension of pre-hydrogenated 10% palladium-on-charcoal hydrogenation catalyst in dioxane at room temperature and atmospheric pressure until two molecular equivalents of hydrogen are absorbed for complete hydrogenation, gives the corresponding 17avinyl or l7a-ethyl derivative.

Where l7a-halo-lower alkynyl-17,8-hydroxy final products are desired, the halo-lower alkynyl substituent can be introduced in many cases by first slowly mixing a polyhaloalkene of the general formula:

H H X '1= Y wherein X represents chlorine or bromine and Y represents chlorine, bromine or trifluoromethyl, such as 1,2-

dichloroethylene, 1,2 dibromoethylene, 1 chloro-3,3,3'-

trifluoropropyl-l-ene, or the like, in anhydrous diethyl ether under an inert nitrogen atmosphere at 0 C., with a solution of methyl lithium in anhydrous diethyl ether (prepared, for example, by adding lithium to methyl iodide in anhydrous diethyl ether solution under an inert nitrogen atmosphere at about 10 C.), then holding the resulting reaction mixture at room temperature, with stirring, for from about 90 minutes to about 2 hours, thus giving the corresponding halo-lower alkynyllithium reagent. Next, the 17-keto steroid VI is slowly added and the resulting reaction mixture is held at room temperature for from about 12 hours to about 18 hours to give the corresponding l7a-halo-lower alkynyl derivative VIII. Where 1,2-dichloroethylene, 1,2-dibromoethylene and 1- chloro-3,3,3-trifluoropropyl-l-ene, respectively, are used, 17a-chloroethynyl, 17a-bromoethynyl and Not-trifluoropropynyl substituents, respectively, are introduced, and the resulting 3,4-dihalornethylene-17a-halo-lower alkynyl-3- rnethoXy-A -estren-17(3-01, when treated with a' silver salt in water in the manner described hereinabove, gives the corresponding A-homo steroid IX. Finally, A-homo- 17a-trifluoropropyny1 A estratrien-l7/8-ol-3-one (IX; R =trifluoropropynyl, R =hydrogen) can be par- XVI tially hydrogenated, if desired, in the manner described hereinabove, to give A-homo-17a (3l',3,3'-trifiuoropropenyl)-A -estratrien l7fl-ol-3-one (IX; R =3,3,3- trifluoropropenyl, R =hydrogen).

The 17 esters of the 170: substituted-Ufi-ols of the present invention can be prepared in known manner, e.g., by reaction at room temperature for 24hours or longer under substantially anhydrous conditions with a mixture of an acyl anhydride and the corresponding acid in the presence of a catalytic amount of p-toluenesulfonic acid. Thus, by reacting A homo-17ot-meth'yl A -estratrien-17fl-ol-3one under these conditions with a mixture of acetic anhydride and acetic acid, the corresponding 17- acetate (IX; R =methyl, R =acetyl) is obtained.

Certain of the 17a-halo-lower alkynyl steroids as well as the corresponding 17a-hydroxypropyriyl and -acyloxypropynyl steroids, of the present invention can be prepared by processes illustrated by the following equations:

In these formulas R X and X have the same meanings as set forth hereinabove, R represents a tetrahydrofuranyl group or a tetrahydropyranyl group, R represents hydrogen or an acyl group and X represents chlorine, bromine or iodine.

In carrying out the first of these processes, the starting material X, e.g., 3,4 dibrornomethylene-l7a-ethynyl-3- methoxy-A -estren-Ufi-ol (X; X=bromine), prepared as described hereinabove, is reacted with dihydrofuran or dihydropyran in the manner described hereinabove to give the corresponding 17-ether XI, e.g., 3,4-dibromomethylene 17oz ethynyl 3 methoxy-17fi-tetrahydropyranyloxy A -estrene (XI; R =tetrahydropyranyl, X=bromine).

A Grignard interchange is then effected between the ethynyl group in this 17-ether and a lower alkylmagnesium halide, such as methylmagnesium chloride, ethylmagnesium bromide, or the like, thus giving the corresponding 17a lower alkynylmagnesium halide intermediate XII, e.g., 3,4 dibromomethylene-l7a-ethynylmagnesium bromide S-methoxy-l7B-tetrahydropyranyloxy-A -estrene (XII; R =tetrahydropyranyl, X and X =bromine). This reaction can be accomplished in known manner, e.g., by reacting the 17-ether and the lower alkylmagnesium halide under substantially anhydrous conditions at reflux temperature in an ether such as tetrahydrofuran, diethyl ether, or the like, as well as mixtures'thereof, for about 6 hours or longer.

The thus-obtained l7a-lower alkynylmagnesium halide intermediate, in the solvent in which it was prepared, is then reacted at a temperature of from about C. to about 40 C., under an inert nitrogen atmosphere, with gaseous formaldehyde to give the corresponding 17ahydroxypropynyl derivative XIII, e.g., 3,4-dibromomethylene-17u hydroxypropynyl-3-methoxy-17,3-tetrahydropyranyloxy-A -estrene (XIII; R =tetrahydropyranyl, X=bromine), which can be obtained from the reaction mixture as such or hydrolyzed with strong acid, e.g., concentrated hydrochloric acid or the like, to give the free 175-01 XIV, e.g., 3,4 dibromomethylene l7a-hydroxypropynyl-3-methoxy A -estren-l7,8-ol (XIV; R and R =hydrogen, X=bromine).

Esterification of the thus-obtained 17a-hydroxypropynyl-l7fi-tetrahydrofuranyloxy or -tetrahydropyranyloxy steroid with an acyl anhydride in pyridine in the manner described hereinabove gives the corresponding l7a-acyloxypropynyl-17B-tetrahydrofuranyloxy or -tetrahydropyranyloxy derivative XIV, e.g., l7a-acetoxypropynyl-3,4-dibromomethylene 3 methoxy-l7p-tetrahydropyranyloxy- XVIII XIX A -estrene (XIV; R =tetrahydropyranyl, R =acetyl, X=bromine), which can then be treated with strong acid, if desired, to give the corresponding l7a-acyloxypropynyll7B-hydroxy derivative XIV, e.g., l7a-acetoxypropynyl- 3,4-dibromomethylene-S-methoxy-A estren 17 3 o1 (XIV; R =hydrogen, R =acetyl, X=bromine).

Similarly, esterification of either the 17x-hydroxypropynyl-17f3-ol XIV or the corresponding 17a-acyloxypropynyl-17fi-ol with a mixture of an acyl anhydride and the corresponding acid in the manner described hereinabove gives the corresponding l7a-acyloxypropynyl-l7fl-acyloxy derivative XIV, e.g., 17a-acetoxypropynyl-3,4-dibromomethylene-3-methoXy-A estren ol 17-acetate (XIV; R and R =acetyl, X=bromine), which can then be partially hydrolyzed, if desired, in known manner, e.g., using a 15% solution of sodium or potassium bicarbonate in aqueous methanol at a temperature of from about 0 C. to about 20 C. for from about 1 hour to about 18 hours, to give the corresponding 17a-hydroxypropynyl- 17;8-acyloxy derivative XIV, e.g., 3,4-dibromomethylenel7a-hydroxypropynyl-3-methoxy-A estren 17/3 ol (XIII; R =hydrogen, R =acetyl, X bromine).

By treating the 17m-hydroxypropynyl-l713-01 XIV, or its ethers or esters, with a silver salt in water in the manner described hereinabove, the corresponding A-homo steroid XV, e.g., A- homo-l7a-hydroxypropynyl-A -estratrien-l7fl-ol-3-one (XV; R and R =hydrogen) or an ether or ester thereof, is obtained.

An A-homo steroid XV having 17fl-acyloxy, -tetrahy drofuranyloxy or -tetrahydropyranyloxy group can then be reacted with from about 1 to 1.5 molar equivalents of Z-chloro-1,1,2-trifluorotriethylamine or the like in an inert organic solvent, e.g., acetonitrile, an ether such as diethyl ether, diisopropyl ether, dioxane or tetrahydrofuran, an aromatic hydrocarbon such as benzene, toluene or Xylene, and the like, as well as mixtures thereof, at a temperature of from about room temperature to reflux temperature for from about 30 minutes to about 24 hours to give the corresponding 17a-monofluoropr0pynyl derivative XVI, e.g., A-homo-17a-monofiuoropropynyl-A -estratrienl7/3-ol-3-one l7-acetate (XVI; R =acetyl).

The thus-prepared 17a-monofluoropropynyl-17fl-acyloxy steroid can be hydrolyzed to the corresponding free 17fi-ol in known manner, e.g., using a boiling 5l0% solution of sodium or potassium hydroxide in aqueous methanol under an inert nitrogen atmosphere, and the corresponding 17-ethers can also by hydrolyzed to the free 17pols in the manner described hereinabove.

A 17a-monofluoropropynyl steroid XVI can also be partially hydrogenated, if desired, in the manner described hereinabove, to give the corresponding 17a-(3'-monofluoropropenyl) derivative XVII, e.g., A homo-17ot-(3'- monofiuoropropenyl)-A -estratrien-17 fl ol 3 one (XVII; R =hydrogen).

In the preparation of 17a-haloethyny1 derivatives, the starting material XVIIIa, e.g., A-homo-17wethynyl-17fltetrahydropyranyloxy-A -estratrien 3 one (XVIII; R =tetrahydropyranyl), prepared as described hereinabove, is reacted with potassium t-butoxide in t-butanol at a temperature of from about C. to about 40 C. for from about 1 to about 24 hours to give the corresponding 17a-ethynylpotassium intermediate XIX.

Where the l7rx-chloroethynyl derivative XX is desired, t-butyl hypochlorite, N-chlorosuccinimide, or the like is added to the solution of the 17u-ethynylpotassium intermediate and the resulting mixture is reacted at a temperature of from about 10 C. to about 40 C. for from about 1 to about 24 hours, thus giving A-homo-17a-chloroethynyl 175 tetrahydropyranyloxy-A -estratrien- 3-one (XX; R -=tetrahydropyranyl, X'=chlorine).

Similarly, where the 17x-bromoethynyl derivative is desired, N-bromosuccinimide or the like is added to the solution of the 17a-ethynylpotassium intermediate and the resulting-mixture is reacted at a temperature of from about 10 C. to about 40 C. for from about 1 to about 24 hours, thus giving A-bromo-17a-bromoethynyl-17/3-tetra hydropyranyloxy-A -estratrien-3-one (XX; R =tetrahydropyranyl, X'=bromine) Acid hydrolysis of the thus-obtained l7-ether, carried out in known manner, gives the free 175-01, e.g., A-homo 17a-chloroethynyl (or bromoethynyl)-A -estratrien- 17B-ol-3-one (XX; R =hydrogen, X'=chlorine or bromine), which can then be esterified with a mixture of an acyl anhydride and the corresponding acid in the manner described hereinabove to give the corresponding 17-esters.

In order that those skilled in the art can more fully understand the present invention, the following examples are set forth. These examples are given solely for the purpose of illustrating the invention, and should not be considered as expressing limitations unless so set forth in the ap pended claims.

Example I A mixture of 5 grams of estrone 3-methyl ether, 150 cc. of anhydrous benzene, 60 cc. of ethylene glycol (previously distilled from sodium hydroxide) and 800 mg. of ptoluenesulfonic acid monohydrate was refluxed for 12 hours, using an adapter to continuously remove the water formed during the reaction. Following this reaction period the reaction mixture was cooled to room temperature and admixed with an aqueous sodium bicarbonate solution. The organic phase was then separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/hexane gave 17 cycloethylenedioxy-S-methoxy- A -estratriene.

Example II A cold solution of 6 grams of l7-cycloethylenedioxy-3- methoxy-ALM -estratriene in 750 cc. of anhydrous diethyl ether was added, with stirring, to 900 cc. of liquid ammonia, and 7.8 grams of lithium wire were then added to the resulting solution, with stirring, over a ten minute period. Following the addition of the last of the lithium, the reaction mixture was stirred at room temperature for 20 minutes, then cautiously treated with 160 cc. of absolute ethanol. Next, after allowing the ammonia to evaporate, water was added and the ether was distilled off. The thus-obtained 17 cycloethylenedioxy 3 methoxy- A -estradiene was collected by filtration, washed with water and dried.

Example III Five grams of 17-cycloethylenedioxy-3-rnethoxy- A -estradiene were added to a solution of 3 gramsof potassium t-butoxide in grains of pure, anhydrous dimethylsulfoxide, contained under an inert nitrogen atmosphere, and the resulting reaction mixture was allowed to stand at room temperature, with stirring, for 6 hours. Following this reaction period the reaction mixture was poured into water and extracted with diethyl ether. The thus-obtained extract was then dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the resulting residue from diethyl ethera-methanol gave 17cycloetl1ylenedioxy-3-methoxy-A -estradiene.

Example IV One gram of 17-cycloethylenedioxy-3methoxy- A -estradiene in 10 cc. of anhydrous benzene was added, under an inert nitrogen atmosphere, to a solution of potassium t-butoxide prepared by dissolving 0.24 gram of potassium in 20 cc. of anhydrous t-butanol, and the resulting mixture was cooled to 0 C. Next, a solution of 1.53 grams of bromoform in 5 cc. of anhydrous benzene was added over a 20 minute period, with stirring, and following this addition the reaction mixture was stirred for another hour. At this point, 100 cc. of benzene were added, and the resulting solution was Washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from benzene/ethanol gave 17-cycloethylenedioxy-3,4-dibromomethylene-3-rnethoxy-A -estrene.

Example V A solution of 500 mg of 17-cycloethylenedioxy-3, 4- dibrornornethylene-3-methoxy-A -estrene in 25 cc. of acetone was admixed with 0.1 cc. of concentrated hydrochloric acid, and the resulting reaction mixture was allowed to stand at room temperature overnight. Following this reaction period the reaction mixture was poured into water and extracted with methylene dichloride. The thus-obtained extract was washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/hexane gave 3,4-dibromomethylene-3methoxy- A -estren-l7-one.

Example VI A solution of 1.4 grams of 3,4-dibromornethylene-3- methoxy-A -estren-l7-one in 200 cc. of aqueous methanol containing 4 molar equivalents of silver nitrate was refluxed for 3 hours. Following this reaction period 200 cc. of water were added, and the resulting solution was then extracted several times with benzene. The thusobtained extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the resulting residue on grams of neutral alumina gave, in the fractions eluted with diethyl etherzbenzene (10% :90%-80% 220% by volume, respectively) A-horno-A -estratriene-3, l'7-dione.

Example VII A solution of 2 grams of sodium borohydride in 30 cc. of methanol was added, with stirring, to a solution of 2 grams of 3,4-dibromomethylene-3-methoxy-A -estren- 17-one in 40 cc. of tetrahydrofuran and the resulting reaction mixture was allowed to stand at room temperature overnight. Following this reaction period excess sodium borohydride was decomposed by the addition of acetic acid, and the resulting solution was concentrated to a small volume under reduced pressure and then diluted with water. Next, the solution was extracted with ethyl acetate and the thus-obtained extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/hexane gave 3,4-dibrornomethylene-3- methoxy-A -estren-Nfi-ol.

Example VIII A solution of 5 grams of 3,4-dibromomethylene-3- methOXy-M -estren-17-one in 250 cc. of thiophene-free benzene was admixed with 27.5 cc. of a 4 N solution of methylrnagnesium bromide in diethyl ether, and the resulting reaction mixture was refluxed, excluding moisture, for 3 hours. Following this reaction period the reaction mixture was cooled and cautiously treated with an excess of an aqueous ammonium chloride solution, then extracted with ethyl acetate. The thus-obtained extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the resulting residue from methylene dichloride/hexane gave 3,4 dibromo-methylene-3-rnethoxy 17u-methyl A estren-17fi-ol.

This procedure was then repeated in every detail but one, namely, methylmagnesium bromide was replaced by equivalent amounts of vinylmagnesium bromide, trifluorovinylma-gnesium bromide and ethynylma gnesiurn bromide, respectively. In each case, the corresponding Not-substituted 17,8-ol, namely, 3,4-dibromomethylene-3- methoxy-l7a-vinyl-A -estren 175-01, 3,4 dibromomethylene-3- methoxy-17a-trifiuorovinyl-A -estren- 17,8- 01, and 3,4-dibromomethylene-l7ot-ethynyl-3-methoxy- A -estren-17B-ol, respectively, was obtained.

Example IX A solution of 1 gram of 3,4-dibromomethylene-3- irnethoxy-A (1 estren-l7-0ne in 30 cc. of anhydrous benzene was added, under an inert nitrogen atmosphere, to a solution of potassium t-amylate prepared by dissolving 1.4 grams of potassium in 30 cc. of t-amyl alcohol. Next, a slow stream of purified acetylene was passed through the solution for 40 hours, following which the solution was diluted with water and extracted several times wit-h benzene. The combined extracts were washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the resultin g residue on 70 grams of alkaline alumina gave, in the hexanetbenzene (2:3, respectively, by volume) fractions, 3,4-dibromo'methylene-l7m ethynl 3 methoxy- A -estren-l7/3-ol, identical to that prepared as described in Example VIII hereinabove.

Example X One gram of 3,4-dibromomethylene-l7a-ethynyl-3- methoxy-n -est-ren-17,8-01 was dissolved in 40 cc. of pyridine containing 400 mg. of pre-hydrogenated 2% palladium-on-calci-um carbonate hydrogenation catalyst, and the resulting suspension was hydrogenated at room temperature and atmospheric pressure until 1.1 molar equivalents of hydrogen had been absorbed. At this point the reaction was stopped by removing the catalyst by filtration through Celite. The catalyst was then washed with ethyl acetate and these washings were added to the filtrate. The combined solution (filtrate plus washings) was then evaporated to dryness under reduced pressure. The resulting residue was dissolved in ethyl acetate and this solution was washed with dilute hydrochloric acid and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Recrystallization of the thus-obtained residue from acetone gave 3,4-dibromometl1ylene-3-methoxy-170t- Viny1-A -estren-17 8-01, identical to that prepared as described in Example VIII hereinabove.

Example XI A solution of 8.5 grams of 1,2-diehloroethylene in 50 cc. of anhydrous diethyl ether was added dropwise, with stirring at 0 C. over a half hour period, to cc. of a 1.4 N solution of methyl lithium in anhydrous diethyl ether, maintained under an inert nitrogen atmosphere, and this mixture was then held at room temperature, with stirring, for an additional 90 minutes.

Next, a solution of 0.5 gram of 3,4-dibromomethylene- 3-methoxy-A -estren-l7-one in cc. of anhydrous diethyl ether was added dropwise, with stirring, over a 15 minute period, following which the resulting reaction mixture was held at room temperature, with stirring, for 18 hours. Following this reaction period the reaction mixture was poured into ice water and then extracted with diethyl ether. The ether extract was then washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. Chromatography on alkaline alumina, using petroleum ether/diethyl ether (8:2, respectively, by volume) as the eluant, followed by recrystallization from methanol, gave l7a-chloroethynyl-3,4-dibromomethylene-3-methoxy-A -estren.

By repeating this procedure using 1,2-dibrom0ethylone and l-chloro-3,3,S-trifiuoropropyl-l-ene, respectively, in place of 1,2-dichloroethylene, the corresponding 17:1- halo-lower alkynyl-l7B-ols, namely, l7a-bromoethynyl- 3,4-dibromomethylene-3-methoxy-A -estren and 3,4- dibromomethylene-l7ottrifluoropropynyl 3 methoxy- A -estren-17,8-ol, respectively.

Example XII The procedure of Example VI hereinabove repeated in every detail but one, namely, 3,4-dibromomethylene-3- methoxy-A -estren-l7B-ol and the corresponding 17asubstituted steroids prepared as described in Examples VIII and XI hereinabove were used as the steroid starting material. In each case, the corresponding A-homo steroid, namely, A-homo-A -estratrien-17a-ol3one, A-homo-17a-methyl-A -estratrien-17fi-ol-3-one, A- homo-l7a-vinyl-A -estratrien-17,8-01 3 one, A- homo-l7ot-trifiuorovinyl-A -estratrien-17(3 ol 3 one, A-horno-l7a-ethynyl-A -estratrien-17,8-01 3 one, A-homo-l7a-chloroethynyl-A -estratrien-l7,6- ol-3-one, A homo-17t t-brornoethynyl-A -estratrien- 17,8-ol-3-one, A-homo-l7a-trifluoropropynyl-A -estratrien-17fl-ol-3-one, respectively, was obtained.

Example XIII A mixture of 1 gram of A-homo-A -estratrien- 17B-ol-3-one, 4 cc. of pyridine and 2 cc. of acetic anhydride was allowed to stand at room temperature overnight. Following this reaction period the reaction mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water and dried. Crystallization from acetone/hexane gave A-homo- A -estratrien-l7fi-ol-3-one l7-acetate.

By repeating this procedure using propionic anhydride, cyclopentylpropionic anhydride, caproic anhydride and enanthic anhydride, respectively, in place of acetic anhydride, the corresponding 17-propi0nate, -cyclopentylpropionate, -caproate and -enanthate, respectively, were obtained.

Example XIV A mixture of 1 gram of A-homo-17a-methyl-A estratrien-l7fl-ol-3-one, 1 gram of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydride was allowed to stand at room temperature for 24 hours. Following this reaction period the reaction mixture was poured into water and stirred until the excess acetic anhydride had hydrolyzed. Next, the product was isolated by extraction with methylene dichloride, and the thus-obtained extract was washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/diethyl ether gave A-homo-l7/3-methyl-A estratrien-17B-ol-3-one l7 acetate.

This procedure was then repeated in every detail but one, namely, A-homo-l7a-methyl-A -estratrien-l7flol-3-one was replaced by the remaining A-homo-l7a-substituted-17B-ols prepared as described in Example XII hereinabove. In each case, the corresponding l7-acetate was obtained.

Similarly, by replacing the mixture of acetic acid and acetic anhydride with mixtures of propionic acid and propionic anhydride, cyclopentylpropionic acid and cyclopentylproprionic anhydride, caproic acid and caproic anhydride, and enanthic acid and enanthic anhydride, respectively, and using each of the A-homo-17a-substituted- 176-ols prepared as described in Example XII hereinabove, in turn, as the steroid starting material, the corresponding 17-propionates, -cyclopentylpropionates, -caproates and -enanthates, respectively, were obtained.

Example XV To a solution of 1 gram of A-homo-A -estratrien- 17fii-o1-3-one in 25 cc. of benzene there was added 4 cc. of dihydropyran. Next, approximately 5 cc. of the mixture of dihydropyran and benzene was distilled off to remove moisture, and the remaining mixture was then cooled to room temperature. To the cooled mixture there was then added 0.1 gram of p-toluenesulfonic acid, and the resulting reaction mixture was held at room temperature for 72 hours. Following this reaction period the reaction mixture was washed with an aqueous 5% sodium carbonate solution and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. The resulting residue was chromatographed by passing it, dissolved in hexane, through a column of neutral alumina, thus giving A-homo-17[Metrahydropyranyloxy-A estratrien-3-one.

By repeating this procedure in every detail but one, namely, replacing dihydropyran with dihydrofuran, the corresponding 1'Zfi-tetrahydrofuranyloxy derivative was obtained.

Similarly, by replacing A-homo-A -estratrien-UB- ol-3-one with the remaining A-homo steroids prepared as described in Example XII hereinabove, and using dihydropyran and dihydrofuran, respectively, as the etherifying agent, the corresponding 17/3-tetrahydropyranyloxy and -tetrahydrofuranyloxy derivatives were obtained.

Example XVI 3,4 dibromomethylene 17a-ethynyl-3-methoxy-A estren-17B-ol was reacted with dihydropyran in the manner described in Example XV hereinabove to give 3,4- dibromomethylene 17a-ethynyl-3-methoxy-17/3 tetrahydropyranyloxy-A -estrene.

A solution of 0.01 mol of this 17-tetrahydropyranyl ether in 50 ml. of anhydrous tetrahydrofuran was admixed with a solution of 0.011 mol of ethylmagnesium bromide in 5 ml. of anhydrous diethyl ether, and the resulting reaction mixture was refluxed for 6 hours, thus giving the corresponding 17ot-ethynylmagnesium bromide intermediate.

The reaction mixture was then cooled and treated under anyhydrous conditions in an inert nitrogen atmosphere at C. with a stream of gaseous formaldehyde (prepared by passing anhydrous nitrogen gas through a flask con taining gaseous paraformaldehyde heated to 180 C. and then passing the nitrogen and entrained gaseous formaldehyde into the reaction mixture) until the reaction was complete, as evidenced by the absence of 17u-ethynylmagnesium bromide starting material on a chromatoplate containing a sample of the reaction mixture. At this point, the reaction mixture was concentrated to about one-fifth of its original volume under reduced pressure, then diluted with water and extracted with methylene dichloride. The thusobtained extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Recrystallization of the resulting residue from acetone/ hexane gave 3,4-dibrornomethylene-l7ahydroxypropynyl-3-rnethoxy l7/3-tetrahydropyranyloxy- A -estrene.

By repeating this procedure in every detail but one, namely, adding 1 cc. of 2 N hydrochloric acid to the concentrated reaction mixture prior to diluting with water, 3,4 dibromomethylene-17u-hydroxypropynyl-3-methoxy- A -estren-17fi-ol was obtained.

Example XVII 3,4-dibromomethylene 17a hydroxypropynyl-3-methoxy-l7B-tetrahydropyranyloxy-A -estrene was esterified with acetic anhydride in pyridine in the manner described in Example XIII hereinabove, thus giving l7u-acetoxypropynyl-3,4-dibromomethylene-3-methoxy-17B-tetrahydropyranyloxy-A -estrene.

By treating the thus-obtained 17a-acetoXypropyny1-17B- tetrahydropyranyloxy steroid with concentrated hydrochloric acid in the manner described in Example XVI hereinabove, 17a acetoxypropynyl-3,4-dibromomethylene-3- methoxy-A -estren-17,8-01 was obtained.

Example XVIII 3,4 dibromomethylene 17a hydroxypropynyl-3-methoxy-A -estren-Ufl-ol was esterified with a mixture of acetic acid and acetic anhydride in the presence of p-toluenesulfonic acid in the manner described in Example XIV hereinabove, thus giving 17wacetoxypropynyl-3, 4- dibromomethylene-3-rnethoxy-A -estren-17fl-ol l7-acetate.

Example XIX A mixture of 1 gram of 17a-acetoxypropynyl-3,4-dibromomethylene-3-methoxy A -estren17,8-0l 17-acetate, cc. of methanol and a solution of 1 gram of potassium bicarbonate in 6 cc. of water was allowed to stand at 0 C. for 18 hours. Following this reaction period the reaction mixture was diluted with water and the resulting precipitate was collected by filtration, Washed with water and dried. Recrystallization from acetone/hexane gave 3,4 dibromomethylene-l7a-hydroxypropynyl-3-methoxy- A -estren-l7,8-ol 17-acetate.

Example XX The procedure of Example VI hereinabove was repeated using 3,4-dibromomethylene-17a-hydroxypropynyl-3 -methoxy- A -estren- 1.7 B-ol,

3,4-dibromomethylene-17a-hydroxypropynyl-3-methoxywas obtained.

Example XXI A mixture of 1 gram of A-homo-17a-hydroxypropynyl- A -estratrien-17fl-ol-3-one 17-acetate, 1.5 molar equivalents of 2-chloro-1,1,Z-trifluorotriethylamine and 30 cc. of anhydrous tetrahydrofuran was allowed to stand at room temperature, with stirring, for 14 hours. Following this reaction period the reaction mixture was evaporated under vacuum at room temperature, and the resulting residue was chromatographed on Fluorisil, using benzene/ethyl acetate mixtures as the eluant, thus giving A- homo 17oz monofiuoropropynyl-A -estratrien175- ol-3one 17-acetate.

By repeating this procedure using A-hom0-17a-hy- 15 droxypropynyl 17fi-tetrahydropyranyloxy-A -estratrien-3-one as the steroid starting material, A-homo-17amonofluoropropynyl 17B tetrahydropyranyloxy A -estratrien-3-one was obtained.

Example XXII A solution of 0.17 gram of potassium hydroxide in 0.2 cc. of water and 2.5 cc. of methanol was added dropwise, with stirring, over a 30 minute period to a boiling solution of 1 gram of A-homo-l7a-rnonofiuoropropynyl- A -estratrien-17/9-ol-3-one 17-acetate in 30 cc. of methanol, contained under an inert nitrogen atmosphere, and the resulting reaction mixture was then boiled for an additional 2 hours. Following this reaction period the reaction mixture was cooled, neutralized with acetic acid and concentrated under reduced pressure. The addition of water to the concentrate gave a precipitate which was collected by filtration, washed with water, dried and then crystallized from acetone/hexane, thus giving A-homo- 17a monofiuoropropynyl A estratrien 17,6- o1-3-one.

Example XXIII The procedure of Example X hereinabove was repeated using A homo-17u-mon0fluoropropynyl-A -estratrien-176-ol-3-one and A-homo-17a-trifluoropropynyl- A -estratrien-l7B-0l-3-one, respectively, as the steroid starting material. In each case, the corresponding 17afiuoropropenyl steroid, namely, A-homo-17a-(3-monofiuoropropenyl) A estratrien 17,8 ol 3 one and A homo 17a (3,3',3 trifiuoropropenyl)- ,5( stratrien17B-ol-3-one, respectively, was obtained.

It Wil be obvious to those skilled in the art that other changes and variations can be made in carrying out the present invention without departing from the spirit and scope thereof as defined in the appended claims.

I claim:

1. A compound represented by the formula:

wherein R is selected from the group consisting of a hydroxyl group, a hydrocarbon carboxylic acyloxy group containing less than 12 carbon atoms, a tetrahydrofuranyloxy group and a tetrahydropyranyloxy group, R is selected from the group consisting of hydrogen, a lower alkyl group, a lower alkenyl group and a lower alkynyl group, and R and R taken together represent a keto group.

2. A-homo-A -estratriene-3,l7-dione.

3. A-homo-A -estratrien-17 3-ol-3-one.

4. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of A-homo-A -estratrien-175-01-3- one.

5. A-homo-17u-methyl-A -estratrien-l7fi-ol-3-one.

6. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of A-homo-17a-methyl-A -estratrienl7fi-ol-3-one.

7. A homo-17ot-vinyl-A -estratrien-17fl-o1-3-one.

8. A homo-17a-trifiuorovinyl-A -estratrien-- ol-3-one.

9. A homo 17a-(3'-monofiuoropropenyl)-A estratlien-l7fi-ol-3-one.

10. A homo 17a-(3',3,3'-trifluoropropenyl) estratrien-l7fi-ol-3-one.

11. A-homo 17a ethynyl-A -estratrien176-01- 3-one.

12. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of A-homo-17a-cthynyl-A -estratrien-17B-ol-3-one.

13. A homo 17a-ethynyl-17 8-tetrahydropyranyloxy- A -estratrien-176-ol-3-one.

14. A-homo 17oz. chloroethynyl-A -estratrien- 17;8-ol-3-one.

15. A-homo-17a-bromoethynyl A estratrien- 17fl-ol-3-one.

16. A homo 17u-monofluoropropynyl-A -estratrien-17B-ol3one.

17. A homo-17a-trifiuoropropynyl-A -estratrien- 17/3-ol-3-one.

18. A homo 17a hydroxypropynyl-17B-tetrahydropyranyloxy-A -estratrien-3-one.

References Cited UNITED STATES PATENTS 2,877,158 3/1959 Agnello et al. 167-65 2,929,763 3/1960 Wettstein et a1. 167-65 3,083,141 3/1963 Camerino et al. 16774 3,117,060 1/ 1964 Bruckner et al. 167-74 3,128,283 4/ 1964 Pappo 260-3432 3,169,136 2/1965 Bowers et a1. 260-3975 3,170,923 2/ 1965 Cross 260-23955 3,210,249 10/1965 Beerstecher et a1. 167-74 OTHER REFERENCES Johnson et al.: Journal American Chem. Soc., vol. 84, pp. 989 (1962).

Herrmann et al.: Experimentia, vol. 19, p. 76 (1963).

Fieser and Fieser: Steroids, Reinhold Pub. Corp, New York (1959), pp. 592-3.

American Drug Index, I. P. Lippincott Co., Philadelphia (1964), p. 48, 225, 318, 467, and 636.

The Merck Index, Merck and Co., Rahway, N.I., (1960), 7th Ed., p. 393, 394, 433, 434, 663, 1018, 1019, and 1640.

Colton et al.: Jour. Amer. Chem. Soc., vol. 79, pp. 1123-7 (1957).

W. R. Nes: Medicinal Chemistry (Burger Ed.) Interscience Pub., Inc., New York 1960), p. 771.

Physicians Desk Reference to Pharmaceutical Specialties and Biologicals, Medical Economics, Inc., Oradell, NJ. (1966), p. 600.

HENRY R. J ILES, Primary Examiner.

J. M. FORD, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,410,874 November 12 1965 Arthur J. Birch It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, lines 35 to 45, the formula should appear as shown below:

Column 4, line 18, "hydroyranyl should read hydropyranyl Column 6, that portion of formula XVII, "A should read H Column 12, line 26, "l7cx-ol" should read 176-01 line 64, "DB-methyl" should read Signed and sealed this l0th'day of March 1970.

('SEAL) I Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

